Epoxide hydrolases convert epoxides to 1,2-dihydrodiols and determine the disposition of reactive epoxide intermediates. Since these epoxides are often the ultimate toxic or carcinogenic form of a protoxin or procarcinogen, the understanding of the nature of epoxide hydrolases and their participation in the deactivation of epoxide intermediates is essential to our ultimate understanding of mechanisms of chemical toxicity and carcinogenesis. Most studies of the role of epoxide hydrolases in xenobiotic metabolism have assumed that a single membrane-bound form of the enzyme exists. We have recently obtained evidence, however, that at least a second membrane-bound epoxide hydrolase exists which has biochemical properties very different from those of the hydrolase previously described. The purpose of the proposed studies is to examine this and other "alternative" epoxide hydrolases, and to assess their involvement in the metabolism and ultimate expression of toxic and/or carcinogenic compounds. The biochemical properties and genetic control of this second epoxide hydrolase will be studied. Its participation in the conversion of active epoxide intermediates of several toxic and carcinogenic compounds will also be studied. We expect ultimately to be able to assess the toxicological importance of this heretofore overlooked enzyme. A second set of experiments will use immunological assays to determine the degree of polymorphism of epoxide hydrolase in man. If, in fact, epoxide hydrolase exists as multiple enzyme forms in man, this may have important toxicological significance, since it would imply genetically determined differences in the capacity of individuals for metabolizing active intermediates of some chemical toxins and carcinogens.